The present invention relates to a method of treating patients at risk of developing atherosclerosis or restenosis.
More particularly, the invention relates to treatment of these patients with a low dose taxol solution to prevent or reduce the development of atherosclerosis or restenosis.
Vascular disease is the leading cause of death and disability in the developed world, particularly afflicting the elderly. In the United States alone, despite recent encouraging declines, cardiovascular disease is still responsible for almost one million fatalities each year and more than one half of all deaths; almost 5 million persons afflicted with cardiovascular disease are hospitalized each year. The cost of this disease in terms of human suffering and of material resources is almost incalculable.
Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to critical body organs, resulting in heart attack, stroke, and kidney failure. Additionally, atherosclerosis causes major complications in those suffering from hypertension and diabetes, as well as tobacco smokers. Atherosclerosis is a form of chronic vascular injury in which some of the normal vascular smooth muscle cells (xe2x80x9cVSMCxe2x80x9d) in the artery wall, which ordinarily control vascular tone regulating blood flow, change their nature and develop xe2x80x9ccancer-likexe2x80x9d behavior. These VSMC become abnormally proliferative, secreting substances (growth factors, tissue-degradation enzymes and other proteins) which enable them to invade and spread into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue served by that artery.
Restenosis, the recurrence of stenosis or artery stricture after corrective surgery, is an accelerated form of atherosclerosis. Recent evidence has supported a unifying hypothesis of vascular injury in which coronary artery restenosis along with coronary vein graft and cardiac allograft atherosclerosis can be considered to represent a much accelerated form of the same pathogenic process that results in spontaneous atherosclerosis (Ip, J. H., et al., (1990) J Am Coll Cardiol, 15:1667-1687; Muller, D. W. M., et al., (1992) J Am Coll Cardiol, 19:418-432). Restenosis is due to a complex series of fibroproliferative responses to vascular injury involving potent growth-regulatory molecules, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), also common to the later stages in atherosclerotic lesions, resulting in vascular smooth muscle cell proliferation, migration and neointimal accumulation.
Restenosis occurs after coronary artery bypass surgery (CAB), endarterectomy, and heart transplantation, and particularly after heart balloon angioplasty, atherectomy, laser ablation or endovascular stenting (in each of which one-third of patients redevelop artery-blockage (restenosis) by 6 months), and is responsible for recurrence of symptoms (or death), often requiring repeat revascularization surgery. Despite over a decade of research and significant improvements in the primary success rate of the various medical and surgical treatments of atherosclerotic disease, including angioplasty, bypass grafting and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of patients (Ross, R. (1993) Nature, 362:801-809).
As a result, a need exists for a successful chemotherapeutic therapy to reduce or prevent artery-blockage. The most effective way to prevent this disease is at the cellular level, as opposed to repeated revascularization surgery which can carry a significant risk of complications or death, consumes time and money, and is inconvenient to the patient.
Microtubules, cellular organelles present in all eukaryotic cells, are required for healthy, normal cellular activities. They are an essential component of the mitotic spindle needed for cell division, and are required for maintaining cell shape and other cellular activities such as motility, anchorage, transport between cellular organelles, extracellular secretary processes (Dustin, P. (1980) Sci. Am., 243: 66-76), as well as modulating the interactions of growth factors with cell surface receptors, and intracellular signal transduction. Furthermore, microtubules play a critical regulatory role in cell replication as both the c-mos oncogene and CDC-2-kinase, which regulate entry into mitosis, bind to and phosphorylate tubulin (Verde, F. et al. (1990) Nature, 343:233-238), and both the product of the tumor suppressor gene, p53, and the T-antigen of SV-40 bind tubulin in a ternary complex (Maxwell, S. A. et al. (1991) Cell Growth Differen., 2:115-127). Microtubules are not static, but are in dynamic equilibrium with their soluble protein subunits, the xcex1- and -tubulin heterodimers. Assembly under physiologic conditions requires guanosine triphosphate (GTP) and certain microtubule associated and organizing proteins as cofactors; on the other hand, high calcium and cold temperature cause depolymerization.
Interference with this normal equilibrium between the microtubule and its subunits would therefore be expected to disrupt cell division and motility, as well as other activities dependent on microtubules. This strategy has been used with significant success in the treatment of certain malignancies. Indeed, antimicrotubule agents such as colchicine and the vinca alkaloids are among the most important anticancer drugs. These antimicrotubule agents, which promote microtubule disassembly, play principal roles in the chemotherapy of most curable neoplasms, including acute lymphocytic leukemia, Hodgkin""s and non-Hodgkin""s Lymphomas, and germ cell tumors, as well as in the palliative treatment of many other cancers.
The newest and most promising antimicrotubule agent under research is taxol. Taxol is an antimicrotubule agent isolated from the stem bark of Taxus brevifolia, the western (Pacific) yew tree. Unlike other antimicrotubules such as colchicine and the vinca alkaloids which promote microtubule disassembly, taxol acts by promoting the formation of unusually stable microtubules, inhibiting the normal dynamic reorganization of the microtubule network required for mitosis and cell proliferation (Schiff, P. B., et al. (1979) Nature 277: 665; Schiff, P. B., et al. (1981) Biochemistry 20: 3247). In the presence of taxol, the concentration of tubulin required for polymerization is significantly lowered; microtubule assembly occurs without GTP and at low temperatures, and the microtubules formed are more stable to depolymerization by dilution, calcium, cold, and inhibitory drugs. Taxol will reversibly bind to polymerized tubulin, and other tubulin-binding drugs will still bind to tubulin even in the presence of taxol.
Taxol has one of the broadest spectrum of antineoplastic activity, renewing serious interest in chemotherapeutic strategies directed against microtubules (Rowinsky, E. K., et al. (1990) Jrnl. of the Nat""l. Cancer Inst., 82:1247-1259). In recent studies, taxol has shown significant activity in advanced and refractory ovarian cancer (Einzig, A. I., et al. (1992) J. Clin. Oncol., 10:1748), malignant melanoma (Einzig, A. I. (1991) Invest. New Drugs, 9:59-64), as well as in cancers of the breast (Holmes, F. A., et al. (1991) JNCI, 83:1797-1805), head and neck, and lung.
Taxol has been studied for its effect in combating tumor growth in several clinical trials using a variety of administration schedules. Severe allergic reactions have been observed following administration of taxol. However, it is has been demonstrated that the incidence and severity of allergic reactions is affected by the dosage and rate of taxol infusion (Weiss, R. B., et al. (1990) J. Clin. Oncol. 8: 1263).
Cardiac arrhythmias are associated with taxol administration, and like allergic reactions, their incidence is affected by the dosage and rate of taxol administration. Sinus bradycardia and Mobitz II arrhythmia will develop in approximately 40% and 5% of patients, respectively, beginning 4-6 hours after the start of a taxol infusion, and continuing for 4-8 hours after its completion. In most patients, the abnormal rhythm is transient, asymptomatic, hemodynamically stable, and does not require cardiac medications or electrical pacing. Additionally, it has been observed that the incidence of severe cardiac events is low in patients receiving taxol alone. Thus, infusion times up to 24 hours have been used in treatment with taxol to decrease the incidence of toxicity and allergic reaction to the drug.
During angioplasty, intaarterial balloon catheter inflation results in deendothelialization, disruption of the internal elastic lamina, and injury to medial smooth muscle cells. While restenosis likely results from the interdependent actions of the ensuing inflammation, thrombosis, and smooth muscle cell accumulation (Ferrell, M., et al. (1992) Circ., 85:1630-1631), the final common pathway evolves as a result of medial VSMC dedifferentiation from a contractile to a secretory phenotype. This involves, principally, VSMC secretion of matrix metalloproteinases degrading the surrounding basement membrane, proliferation and chemotactic migration into the intima, and secretion of a large extracellular matrix, forming the neointimal fibropoliferative lesion. Much of the VSMC phenotypic dedifferentiation after arterial injury mimics that of neoplastic cells (i.e., abnormal proliferation, growth-regulatory molecule and protease secretion, migration and basement invasion).
Although others have investigated the use of the antimicrotubule agent colchicine in preventing restenosis, opposite conclusions have been reported (See Currier, et al., xe2x80x9cColchicine Inhibits Restenosis After Iliac Angioplasty In The Atherosclerotic Rabbitxe2x80x9d (1989) Circ., 80:II-66; O""Keefe, et al., xe2x80x9cIneffectiveness Of Colchicine For The Prevention Of Restenosis After Coronary Angioplastyxe2x80x9d (1992) J. Am. Coll. Cardiol., 19:1597-1600). The art fails to suggest the use of a microtubule stabilizing agent such as taxol in preventing or reducing this disease. Thus, the method of the present invention is to prevent or reduce the development of atherosclerosis or restenosis using a microtubule stabilizing agent such as taxol or a water soluble taxol derivative. This microtubule stabilizing mechanism of atherosclerosis or restenosis prevention is supported by the analogous results in experiments on cellular proliferation and migration using taxol and 2H2O (deuterium oxide), which exert comparable microtubule effects via different underlying mechanisms.
Accordingly, an object of this invention is to provide a method to reduce or prevent the development of atherosclerosis or restenosis using treatment with a drug which promotes highly stabilized tubule formation.
An additional object of this invention is to provide a method of preventing or reducing atherosclerosis or restenosis using a pharmaceutical preparation containing a low dosage of taxol or water soluble taxol derivative.
All references cited are herein incorporated by reference.
In accordance with these and other objects of the present invention, a method of preventing or reducing atherosclerosis or restenosis is provided, which comprises treatment with a therapeutically effective amount of a microtubule stabilizing agent such as taxol or a water soluble taxol derivative. A therapeutically effective amount of agent is an amount sufficient to prevent or reduce the development of atherosclerosis or restenosis.
This method provides an effective way of preventing or reducing the development of atherosclerosis or restenosis in those patients susceptible to such disease. Additionally, because of the low dose of chemotherapeutic agent used, the chance of a patient developing adverse reactions is potentially reduced.